Autoimmune diseases are prevalent in women during child-bearing years, yet pregnant women are excluded from experimental treatments for autoimmune diseases because of unknown effects on the fetus and because of changes that occur in the immune system during pregnancy. These changes make it difficult to predict how the maternal immune system would respond to tolerance-inducing strategies. This project has been created to address questions concerning how the maternal immune system changes during pregnancy to accept the "foreign" fetus and whether the maternal immune system is tolerant to or simply ignores fetal antigens. Female mice were mated with either syngenic or allogeneic males, then lymphoid tissues were evaluated for phenotypic changes in the T cells that would indicate exposure to fetal antigens. There were no detectable changes in T cell receptor usage or expression of costimulatory molecules. However, expression of early activation markers and memory markers was significantly altered in both syngeneic and allogeneic pregnancy. Experiments with pseudopregnant females reveals that modulation of these markers was due to changes in pregnancy hormones and not a result of exposure to fetal antigens. Future studies will address how changes in these activation and memory markers that are modulated by pregnancy-related hormone levels affect maternal T cell responsiveness. Because of the extremely low precursor frequencies of paternal antigen-specific cells, experiments were also performed with pregnant female transgenic mice in which the majority of T cells express a transgenic T cell receptor specific for the male antigen, H-Y. Analysis of the fate of these paternal antigen-specific T cells in pregnant mice reveals an overall decrease in the number of H-Y specific T cells, specifically in the spleen. This decrease is still observed at 5 days post-partum, suggesting that H-Y- specific T cells that encounter antigen are activated and deleted. This is the first report of tolerance induction to fetal antigens by deletion of fetal-reactive T cells during pregnancy. In vitro responsiveness to H-Y is also diminshed at this time, potentially because the remaining H-Y specific T cells that have escaped deletion may be anergic. This finding is not due to hormonal effects because analysis of TCR transgenic pregnant females of the wrong MHC phenotye, which therefore cannot recognize H-Y, reveals no decrease in H-Y specific T cells and no diminished responsiveness in vitro. Future studies will address how these observed changes, both antigen-specific and nonspecific, in the maternal immune system during pregnancy will affect tolerance induction in mouse models of autoimmune disease and what effect maternal tolerance induction during pregnancy will have on the fetus.